Mitochondrion is at the heart of the now widely acknowledged “free radical theory of ageing” and thus involved in the pathogenesis of nearly all ageing-associated diseases, including cardiovascular disease, neurodegenerative diseases (Parkinson's disease, Alzheimer's disease and the like), cancer and diabetes, as well as tissue dysfunctions of ischemic origin. This theory states that the accumulation of damages caused by reactive oxygen species (ROS) impacts numerous cellular functions, in particular mitochondrial functions, which are essential for energy supply and optimal cellular functioning. Mitochondria thus appear as the primary targets of ROS since optimal cellular functioning is crucial for providing the energy for a cell to repair itself.
Interestingly, mitochondria are the major source of reactive oxygen species (ROS) and are thus particularly targeted by oxidative damage. Consequently, mitochondrial self-production of ROS causes oxidative damage that contributes to mitochondrial dysfunction and cell death.
Various antioxidants have been tested with regard to the physiological and pathological roles of ROS. Antioxidant research has provided numerous natural and designed molecules that modulate ROS with various selectivity against the different origins of ROS, being physiological (cellular signalling) or pathological. However, although ROS have been related to numerous diseases, and antioxidants have shown promises in many preclinical experiments, nearly all clinical trials of antioxidant-based therapeutics have shown limited efficacy (Orr et al., 2013. Free Radic. Biol. Med. 65:1047-59).
In addition, several recent studies have also demonstrated that too much reduction of ROS in cells is deleterious and it appears that an adequate balance of ROS production is necessary for cell functioning (Goodman et al., 2004 Dec. 1. J. Natl. Cancer Inst. 96(23):1743-50; Bjelakovic G et al., 2007 Feb. 28. JAMA. 297(8):842-57). As a consequence, there is a growing interest in the selective inhibition of ROS production by mitochondria that would not affect cellular signaling by cytosolic ROS production.
As mitochondrial oxidative damage contributes to a wide range of human diseases, antioxidants designed to be accumulated by mitochondria in vivo have been developed. The most extensively studied of these mitochondria-targeting antioxidants is MitoQ, which contains an antioxidant quinone moiety covalently attached to a lipophilic triphenylphosphonium cation. MitoQ has now been used in a range of in vivo studies in rats and mice and in two phase II human trials. Conditions of high ROS production are now better characterized. It appears that ROS may be produced at multiple sites of the respiratory chain in mitochondria (Quinlan C L et al., 2013 May 23. Redox Biol. 1:304-12). Maximal superoxide/H2O2 production occurs under conditions of high reduction of electron transporters, mainly quinones, and high values of mitochondrial membrane potential. Paradoxically, these conditions are satisfied when mitochondrial oxidative phosphorylation is low (low muscle contraction) or under low oxygen conditions (hypoxia).
The Applicant demonstrates here that AOL (Anethole trithione) does not act as a classical unspecific antioxidant molecule but more interestingly as a direct selective inhibitor of the production of oxygen radicals (ROS) predominantly at site IQ of complex I of the mitochondrial respiratory chain, the main mitochondrial site of ROS production and the main responsible site for mitochondrial dysfunctions. In addition, the Applicant demonstrates here that AOL does not affect mitochondrial oxidative phosphorylation suggesting the absence of any adverse side effects and the possibility to treat and/or prevent diseases related to free oxygen-radicals in a long term manner. AOL is therefore the first known drug authorized for human use (FDA-marketing authorization) that prevents mitochondria from producing ROS at site IQ.